Bone Density Increased During Bisphosphonate Therapy in Sisters With SGMS2 Mutation

A longitudinal clinical evaluation of two young sisters affected by an exceptionally rare monogenic skeletal disorder has revealed substantial gains in bone mineral density alongside the absence of new low-trauma fractures during sequential intravenous bisphosphonate therapy, even as their spinal vertebrae followed markedly diverging structural paths. The siblings carry a recurrent heterozygous nonsense mutation known as c.148C>T, p.(Arg50Ter) in the SGMS2 gene, which encodes the enzyme sphingomyelin synthase 2. Pathogenic alterations in this gene are responsible for calvarial doughnut lesions with bone fragility, a scarce autosomal dominant condition characterized by childhood-onset skeletal fragility, reduced bone mass, sclerotic skull anomalies, and occasionally cranial nerve palsies.

The older sibling initially presented for specialized medical evaluation at the age of nine years and zero months after her family noticed a firm nodular prominence over her left frontal bone approximately fifteen months earlier following an episode of minor head trauma. Diagnostic ultrasonography confirmed the presence of a distinct bony elevation, prompting comprehensive cranial computed tomography and magnetic resonance imaging. Those radiological investigations identified multiple sclerotic calvarial lesions, the most prominent of which measured approximately seventeen by eleven millimeters centrally in the frontal bone situated above the crista galli, accompanied by smaller sclerotic foci in the parietal bones. Crucially, these cranial lesions exhibited neither restricted diffusion nor abnormal contrast enhancement. Extensive rheumatological and oncological evaluations yielded entirely normal results, and initial genetic testing ruled out LEMD3-related osteopoikilosis, leaving the underlying etiology unidentified during the opening stages of the investigative workup.

Subsequent physical examination of the older sister revealed overt postural asymmetry involving her shoulders, scapulae, and iliac crests, prompting clinicians to conduct a comprehensive pediatric skeletal assessment. Dual-energy X-ray absorptiometry, commonly referred to as DXA, demonstrated markedly depressed bone mineral density, yielding an age- and sex-adjusted total body less head Z-score of -2.7 and a lumbar spine Z-score spanning vertebrae L1 through L4 of -3.3. Given these profoundly depressed densitometric measurements in a child displaying unusual cranial lesions, pediatric endocrinologists performed spinal radiography despite the child having never experienced low-trauma long-bone fractures. These spinal radiographs revealed multiple vertebral compression fractures throughout both the thoracic and lumbar segments, definitively fulfilling diagnostic criteria for pediatric osteoporosis. Whole-exome sequencing subsequently uncovered the heterozygous pathogenic SGMS2 c.148C>T nonsense variant after targeted evaluations of LEMD3 and leukocyte-derived GNAS failed to detect causative mutations, thereby securing the definitive molecular diagnosis.

The family’s diagnostic trajectory soon expanded to include the younger sister, who developed a similar nodular calvarial prominence at approximately six years of age, shortly after cranial lesions had been recognized in her older sibling. Targeted clinical and skeletal evaluations performed when she reached six years and eight months of age revealed no overt postural deformities, but DXA screening similarly detected profound skeletal demineralization. Her total body less head bone mineral density Z-score measured -2.3, while her lumbar spine Z-score stood at -3.1. Despite having no documented personal history of peripheral fragility fractures, spinal radiographs demonstrated definitive vertebral compression fractures involving thoracic vertebrae T9 and T11 as well as lumbar vertebra L1. Targeted Sanger sequencing rapidly corroborated the presence of the identical heterozygous familial SGMS2 c.148C>T, p.(Arg50Ter) variant, demonstrating shared molecular pathology between the two siblings.

Pedigree analysis uncovered evidence of phenotypic variability and vertical transmission within the family lineage. The girls’ father carried the identical heterozygous SGMS2 nonsense mutation and possessed a past medical history notable for facial nerve palsy, a neurological complication previously recognized in literature describing SGMS2-associated skeletal disorders. Cranial imaging performed on the father demonstrated characteristic calvarial abnormalities, including localized calvarial thickening and focal areas of reduced bone density, consistent with autosomal dominant inheritance. Neither paternal grandparent underwent genetic testing for the familial SGMS2 variant.

Prior to commencing pharmacological bone-strengthening protocols, both children began daily oral supplementation consisting of elemental calcium, dosed at 400 milligrams daily for the older sister and 200 milligrams daily for the younger sister, combined with 2,000 international units of daily vitamin D. Intravenous bisphosphonate therapy was initiated at nine years and five months of age in the older sister and at six years and ten months in the younger sister. Both children received nine cycles of intravenous pamidronate administered at four-month intervals, with each standard cycle delivering three consecutive daily four-hour infusions of one milligram per kilogram per day, totaling three milligrams per kilogram per cycle, following an initial test infusion of 0.5 milligrams per kilogram. Because of a nationwide pamidronate supply shortage in Poland, their clinical management was subsequently switched to intravenous zoledronic acid, which was administered across three consecutive cycles spaced six months apart as thirty-minute infusions with escalating doses of 0.0125, 0.025, and 0.05 milligrams per kilogram.

An unexpected clinical development emerged during the course of antiresorptive therapy when both sisters were independently diagnosed with concomitant celiac disease. The condition was formally diagnosed at ten years and three months of age in the elder sister and at seven years and eight months in the younger sister, well after the initial skeletal damage had been documented and intravenous pamidronate treatment had already commenced. Both patients subsequently followed a gluten-free diet, with serial anti-tissue transglutaminase antibody measurements indicating good disease control.

Serial densitometric surveillance across the multi-year treatment period documented substantial longitudinal increases in both absolute bone density and age-standardized Z-scores. In the older sibling, total body less head areal bone mineral density rose from a baseline of 0.498 grams per square centimeter with a Z-score of -2.7 to 0.820 grams per square centimeter with a Z-score of -0.9 at thirteen years and ten months of age, while her lumbar spine density surged from 0.394 grams per square centimeter with a Z-score of -3.3 up to 0.966 grams per square centimeter with a Z-score of -0.6. The younger sibling demonstrated comparable gains, with her total body less head density increasing from 0.452 grams per square centimeter with a Z-score of -2.3 to 0.739 grams per square centimeter with a Z-score of -0.7 at eleven years and three months, and her lumbar spine density improving from 0.420 grams per square centimeter with a Z-score of -3.1 to 0.803 grams per square centimeter with a Z-score of -0.5.

Despite this shared upward trajectory in densitometric scores, closer inspection revealed distinct differences in how each child progressed through follow-up. The younger sister exhibited a temporary dip in her Z-scores between eight years eleven months and nine years eleven months, where her lumbar spine score dropped transiently from -1.0 to -1.3 and her total body score slipped from -1.4 to -1.6 before rebounding strongly to final values of -0.5 and -0.7. Over the same total timeframe, both sisters maintained linear growth with height standard deviation scores consistently remaining above -2.0. The older sister grew from 127.5 centimeters to 160.5 centimeters with height velocity ranging between 4.2 and 9.2 centimeters per year, progressing to Tanner stage IV pubertal maturation and reaching menarche at twelve years and five months. In contrast, the younger sister grew from 114.0 centimeters to 138.0 centimeters with annualized height velocities between 1.7 and 8.5 centimeters per year, remaining premenarchal at Tanner stage II.

Most strikingly, serial spinal radiographs documented a profound discordance between densitometric recovery and anatomical vertebral remodeling between the two siblings. Neither child suffered an incident low-trauma fragility fracture throughout follow-up, though the older sibling sustained an isolated high-energy upper-limb fracture requiring surgical intervention following substantial mechanical trauma. In that older sister, serial spinal imaging confirmed evident vertebral reshaping and improved bone mineralization across her thoracic spine, leaving only modest residual height loss at vertebrae T6 and T7. In sharp contrast, spinal radiographs of the younger sister demonstrated persistent, severe height reduction across multiple thoracic vertebrae and lumbar vertebra L2, showing no definitive morphological restitution or characteristic bisphosphonate-associated endplate appositional lines despite her dramatic lumbar spine Z-score improvement from -3.1 to -0.5.

Biochemical safety monitoring throughout all twelve bisphosphonate cycles confirmed that the treatment protocol was well tolerated by both children without severe adverse events. Asymptomatic, transient reductions in serum ionized calcium were occasionally detected four hours after infusions, which clinicians successfully managed with brief supplemental oral calcium without any symptomatic hypocalcemia. Total serum calcium remained between 2.25 and 2.59 millimoles per liter in the older sister and 2.35 to 2.68 millimoles per liter in the younger sister, while serum 25-hydroxyvitamin D, parathyroid hormone, and phosphate stayed within expected clinical limits. Circulating bone turnover markers, specifically osteocalcin and serum CrossLaps, fluctuated broadly across follow-up without exhibiting a monotonic downward trend, reinforcing expert consensus that bone turnover biomarkers show wide physiological variability during childhood growth and cannot serve as standalone measures of drug efficacy.

The authors underscored that while these findings illustrate clear densitometric gains and fracture protection during antiresorptive therapy, substantial physiological and methodological limitations preclude attributing the positive outcomes solely to bisphosphonates. In growing children with monogenic osteopenic conditions, spinal remodeling depends inherently on residual growth velocity, fracture severity, and pubertal timing rather than pharmacological intervention alone. Furthermore, the simultaneous introduction of a gluten-free diet for celiac disease undoubtedly aided skeletal mineral accrual, making it impossible to separate dietary, endocrine, and antiresorptive contributions. Finally, because bone tissue studies in SGMS2 mutations show intrinsic matrix disorganization and disrupted lacunocanalicular architecture that antiresorptive agents cannot directly repair, the researchers cautioned that normalized DXA scores do not guarantee normal bone material quality, underscoring the necessity of integrated, multidimensional assessments in pediatric skeletal fragility.

Subject of Research: Longitudinal skeletal outcomes of intravenous bisphosphonate therapy in SGMS2-associated osteoporosis

Article Title: Case Report: Longitudinal skeletal outcomes during intravenous bisphosphonate therapy in two siblings with SGMS2-associated osteoporosis and calvarial doughnut lesions

Article References: Łupińska, A., Aszkiełowicz, S., Chlebna-Sokół, D., Stawerska, R., Zygmunt, A., & Michałus, I. (2026). Case Report: Longitudinal skeletal outcomes during intravenous bisphosphonate therapy in two siblings with SGMS2-associated osteoporosis and calvarial doughnut lesions. Frontiers in Endocrinology, 17, Article 1995754. https://doi.org/10.3389/fendo.2026.1995754

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1995754

Keywords: SGMS2, pediatric osteoporosis, calvarial doughnut lesions, pamidronate, zoledronic acid, bone mineral density, dual-energy X-ray absorptiometry, vertebral compression fractures, monogenic skeletal fragility, sphingomyelin synthase 2, celiac disease, vertebral reshaping, bone turnover markers, intravenous bisphosphonates, rare bone disease, case report