Abstract
Osteomalacia is a systemic metabolic bone disease. Hypophosphatemia is one of the most important causes of impaired mineralization. Here, we describe a case of osteomalacia associated with atypical renal tubular acidosis. A 43-year-old woman was admitted to our hospital due to sustained unrelieved bilateral flank pain. She had a history of fragile fracture with vitamin D deficiency and had been treated with active vitamin D. On admission, she presented with hypophosphatemia, hypocalcemia, high bone-specific alkaline phosphatase level, bone pain, and low bone mineral density. Multiple areas of uptake were also confirmed by bone scintigraphy, and she was diagnosed with osteomalacia. An increased dose of alfacalcidol was initiated for her vitamin D deficiency; her symptoms remained unstable and unrelieved. Her blood gas examination revealed metabolic acidosis without an increase in the anion gap (HCO3− 11.8 mEq/L, anion gap 3.2 mEq/L). Tubular dysfunction, tubular damage, kidney stones, and inadequate urinary acidification were all observed, suggesting the presence of renal tubular acidosis from a combination of both distal and proximal origin. She also had overt proteinuria, decreased renal function, and hypothalamic hypogonadism. In addition to alfacalcidol, sodium bicarbonate and oral phosphorus supplementation were initiated. After this prescription, her pain dramatically improved in association with the restoration of acid–base balance and electrolytes; renal dysfunction and proteinuria were unaltered. This case indicated that careful assessments of tubular function and acid–base balance are essential for the management of osteomalacia in addition to the evaluation of the calcium/phosphate balance and vitamin D status.
Keywords: Osteomalacia, Renal tubular acidosis, Vitamin D deficiency, Chronic kidney disease, Case report
Introduction
Osteomalacia is a systemic metabolic bone disease characterized by impaired mineralization of the bone matrix [1]. Patients with osteomalacia exhibit bone pain and muscle weakness and present pigeon chest, spinal curvature, and pseudofractures (Looser’s zone) in severe cases. Without proper diagnosis and management, patient quality of life can be significantly diminished. Hypophosphatemia is one of the most important causes of impaired mineralization. The etiologies causing hypophosphatemia are involved in impaired actions of vitamin D metabolites, renal tubular dysfunction, excessive action of fibroblast growth factor 23 (FGF23), and phosphate (P) depletion [1].
Renal tubular acidosis (RTA) presents normal anion gap metabolic acidosis caused by an impaired mechanism of the renal tubules that facilitates the reabsorption of HCO3−, the secretion of H+, or both [2]. In general, RTA is classified into three subtypes: type 1 (distal) RTA (dRTA) caused by impaired H+ excretion in the distal tubule, type 2 (proximal) RTA (pRTA) caused by impaired resorption of HCO3− in the proximal tubule, and type 4 (hyperkalemia) RTA caused by aldosterone dysfunction [2]. The combination of pRTA and dRTA is a rare disorder and is associated with marble bone disease, congenital type II carbonic anhydrase deficiency [3]. Urinary acidification is impaired in patients with dRTA, and even in the presence of acidosis, urine pH is higher than 5.5. On the other hand, although the resorption of HCO3− is impaired in patients with pRTA, distal urinary acidification mechanisms remain, and urine pH is 5.5 or lower [2]. RTA has been identified as one of the causes of osteomalacia.
Here, we present a case of osteomalacia associated with atypical RTA with overt proteinuria and decreased renal function. Administration of alfacalcidol, oral phosphorus preparation, and sodium bicarbonate improved bone pain, metabolic acidosis, and excess urinary calcium (Ca) excretion.
Case presentation
A 43-year-old woman was admitted to our hospital with strong bilateral flank pain. Two years prior to visiting our hospital, at the age of 41, she visited her primary care doctor with bilateral abdominal and thigh pain. At that time, she demonstrated hypocalcemia (corrected calcium (cCa) 8.3 mg/dL), hypophosphatemia (P 2.3 mg/dL), high bone-specific alkaline phosphatase (BAP) level (BAP 74.4 μg/L), and vitamin D deficiency (25-hydroxy-vitamin D (25(OH)D) 7 ng/mL). In addition, her bone mineral density (BMD) was extremely low; the T score of lumbar spine 2–4 (LS) was − 3.2 and that of femoral neck (FN) was − 3.9. Bone scintigraphy revealed multiple areas of uptake in bilateral costal cartilage (Fig. 1), and computed tomography (CT) scan identified multiple fractures in the same location. From these findings, she was diagnosed with pathological fractures due to osteomalacia. Treatment with alfacalcidol was initiated; subsequently, her bilateral abdominal pain and BMD were temporarily ameliorated. However, at the age of 42, she had amenorrhea; thereafter, her pain recurred, and she was referred to our hospital. She had history of several fragile fractures: cracked pubic bone at the age of 26, little toe fracture at the age of 35, rib fracture at the age of 38, and bilateral costal cartilage fractures at the age of 41 (the time of diagnosis with osteomalacia). She took stimulant laxatives for constipation on a daily basis. She had no history of disease or drug use that could cause RTA. She did not have a family history of fractures or bone disease; both her mother and brother had a urinary stone. The first menstruation was at the age of 12. Her dietary habit was well balanced. Her body weight had not fluctuated much for several years.
Fig. 1.
Bone scintigraphy. Multiple areas of uptake in bilateral costal cartilage both 2 years ago and our hospital data were observed
Her height was 160 cm, her body weight was 43.4 kg, and her body mass index was 16.9 kg/m2. Her blood pressure was 98/63 mmHg, pulse rate was 42 beats/min, and body temperature was 36.5 °C at her first visit. Her grip strength was 21.6/18.2 kg. There was no lower leg edema. Other physical findings were unremarkable.
The laboratory data are shown in Table 1. Despite taking alfacalcidol, hypocalcemia, mild hypophosphatemia, and high BAP levels remained. Bone resorption markers were also elevated. In addition, her BMD was even lower than that 1 year ago (Table 2). Bone scintigraphy revealed multiple areas of uptake in bilateral costal cartilage (Fig. 1), consistent with osteomalacia. The presence of primary hyperparathyroidism, myeloma, and malignant tumors was excluded. The FGF23 level was below the detection limit. She did not have any episodes of persistent diarrhea or malabsorption. Among her laboratory data, vitamin D deficiency emerged as the candidate factor causing osteomalacia.
Table 1.
Baseline laboratory data
| Parameter | Case | Reference range |
|---|---|---|
| Arterial blood gas | ||
| pH | 7.232 | 7.35–7.45 |
| pO2, mmHg | 117 | 83–108 |
| pCO2, mmHg | 29.2 | 35–48 |
| HCO3−, mEq/L | 11.8 | 21–28 |
| Na, mEq/L | 140 | 138–145 |
| K, mEq/L | 3.8 | 3.6–4.8 |
| Cl, mEq/L | 125 | 101–108 |
| Base excess, mEq/L | − 14.3 | − 3 to + 3 |
| Lactic acid, mg/dL | 2.0 | 4.5–13.5 |
| Anion gap, mEq/L | 3.2 | 8–16 |
| Urinalysis | ||
| pH | 6.0 | 4.5–7.5 |
| Glucose | – | – |
| Blood | – | – |
| Pro/Crea, g/gCr | 1.38 | < 0.03 |
| FENa, % | 1.24 | < 1.0 |
| FEK, % | 17.8 | 10–20 |
| FECl, % | 4.49 | < 1.0 |
| Ca/Crea (mg:mg) | 0.90 | < 0.21 |
| %TRP, % | 78 | 80–90 |
| TmP/GFR, mg/dL | 1.95 | 2.3–4.3 |
| FEMg, % | 18.7 | < 2.0 |
| FEUA, % | 19.6 | 5.5–11.0 |
| NAG, U/L | 7.1 | 0.7–11.2 |
| β2m, μg/L | 14,998 | 5–253 |
| Anion gap, mEq/L | − 179 | < 0 |
| Complete blood count | ||
| WBC, /μL | 4730 | 3300–8600 |
| Hb, g/dL | 12.1 | 11.6–14.8 |
| Plt, /μL | 26.1 × 104 | 15.8–34.8 × 104 |
| Serum characteristics | ||
| Alb, g/dL | 3.9 | 4.1–5.1 |
| AST, IU/L | 23 | 13–30 |
| ALT, IU/L | 18 | 7–23 |
| LDH, IU/L | 193 | 124–222 |
| ALP, IU/L | 507 | 106–322 |
| HbA1c, % | 5.4 | 4.9–6.0 |
| BUN, mg/dL | 11.4 | 8.0–20.0 |
| Crea, mg/dL | 0.86 | 0.46–0.79 |
| eGFR, mL/min/1.73 m2 | 57.5 | > 60 |
| UA, mg/dL | 2.6 | 2.6–5.5 |
| Na, mEq/L | 140 | 138–145 |
| K, mEq/L | 4.0 | 3.6–4.8 |
| Cl, mEq/L | 119 | 101–108 |
| cCa, mg/dL | 8.2 | 8.8–10.1 |
| P, mg/dL | 3.1 | 2.7–4.6 |
| Mg, mg/dL | 2.7 | 1.8–3.6 |
| Cu, μg/dL | 149 | 71–132 |
| Ceruloplasmin, mg/dL | 33 | 21–37 |
| Intact PTH, pg/mL | 57 | 10–65 |
| 25(OH)D, ng/mL | 13.6 | > 30 |
| 1,25(OH)2D, pg/mL | 79 | 20–60 |
| FGF23, mg/dL | < 10 | 16–69 |
| Immunoglobulin | Normal | |
| Complement | Normal | |
| Antinuclear antibody | – | – |
| Anti-SS-A/SS-B autoantibody | – | – |
| Anti-mitochondrial antibody | – | – |
| PAC, pg/mL | 257 | 30–159 |
| PRA, ng/mL | 3.2 | 0.2–2.3 |
| Bone metabolism markers | ||
| BAP, ng/mL | 37.8 | 3.8–22.6 |
| u-NTX, nMBCE/mM | 207 | < 40 |
| TRACP-5b, mU/dL | > 1500 | 120–420 |
Na sodium, K potassium, Cl chlorine, Pro protein, Crea creatinine, FENa fractional excretion of sodium, FEK fractional excretion of potassium, FECl fractional excretion of chlorine, Ca calcium, TRP tubular reabsorption of phosphate, TmP/GFR ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, FEMg fractional excretion of magnesium, FEUA fractional excretion of uric acid, NAG N-acetyl glucosaminidase, β2m beta 2 microglobulin, WBC white blood cell, Hb hemoglobin, Plt platelet, Alb albumin, AST aspartate transaminase, ALT alanine aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, HbA1c hemoglobin A1c, BUN blood urea nitrogen, eGFR estimated glomerular filtration rate, UA uric acid, cCa corrected calcium, P phosphate, Mg magnesium, Cu copper, PTH parathyroid hormone, 25(OH)D 25-hydroxy-vitamin D, 125(OH)2D 125-hydroxy-vitamin D, FGF23 fibroblast growth factor 23, SS-A/B Sjögren’s syndrome-related antigen A/B, PAC plasma aldosterone concentration, PRA plasma renin activity, BAP bone-specific alkaline phosphatase, u-NTX urine type I collagen cross-linked N-telopeptide, TRACP-5b tartrate-resistant acid phosphatase 5b
Table 2.
Transition of BMD
| Parameter | 2 years ago | 1 year ago | Our hospital data |
|---|---|---|---|
| LS BMD (g/cm2) | 0.628 | 0.840 | 0.639 |
| T score | − 3.2 | − 1.7 | − 3.4 |
| Z score | − 3.0 | − 0.9 | − 2.9 |
| FN BMD (g/cm2) | 0.360 | 0.428 | 0.382 |
| T score | − 3.9 | − 3.3 | − 3.7 |
| Z score | − 3.6 | − 3.0 | − 3.5 |
| 1/3R BMD (g/cm2) | ND | ND | 0.561 |
| T score | ND | ND | − 2.0 |
| Z score | ND | ND | − 1.9 |
BMD bone mineral density, LS lumbar spines 2–4, FN femoral neck, 1/3R distal third of the radius, ND no data
She had metabolic acidosis without an increase in the anion gap on her blood gas with hyperchloremia. She did not have immunoglobulin abnormalities. Her renin and aldosterone levels were somewhat elevated, suggesting secondary aldosteronism. All of the antinuclear antibody, Sjögren’s syndrome-related antibodies, and anti-mitochondrial antibodies were negative. Wilson disease, cystinosis, tyrosinemia, and galactosemia were also excluded. She had overt proteinuria and decreased renal function (estimated glomerular filtration rate (eGFR) 57.3 mL/min/1.73 m2). Increased urinary excretion of each electrolyte, uric acid, and β2 microglobulin (β2m) suggested the presence of pRTA. In addition, urine pH was higher than 5.5, and kidney stones were observed on CT (Fig. 2), suggesting the presence of dRTA as well. Her negative urinary anion gap suggested the increased excretion of NH4+ into the urine; such data were inconsistent with her urine pH findings by which urinary acidification was significantly diminished. The absence of hypokalemia was atypical for either proximal or distal RTA as well.
Fig. 2.
Abdominal computed tomography scan. Bilateral kidney stones were observed
Although the underlying cause and subtype of RTA were not identified, RTA and renal dysfunction were the major pathological causes. Based on these findings, we diagnosed osteomalacia induced by atypical RTA (the combination of proximal and distal types) with vitamin D deficiency. In addition, hypothalamic hypogonadism, diagnosed by luteinizing hormone-releasing hormone test, and secondary amenorrhea due to emaciation decreased BMD in the past 1 year. Likely, her osteomalacia was not ameliorated since her metabolic acidosis induced excretion of Ca ions into urine despite the use of alfacalcidol.
Treatment with sodium bicarbonate was initiated to correct metabolic acidosis (Fig. 3). Alfacalcidol was continued, and oral phosphorus supplementation was also added. Soon after this prescription, her bilateral flank pain was significantly relieved, and she was discharged from the hospital. During the outpatient follow-up, the amount of Ca excretion into urine fluctuated partially due to unstable adherence to her medication, although her pain remained completely relieved. Additionally, mild renal impairment with proteinuria and amenorrhea remained.
Fig. 3.
Clinical course. Treatment with alfacalcidol was initiated when the patient was diagnosed with osteomalacia and her pain was not completely improved. After amenorrhea, the pain recurred. She was admitted to our hospital (X day), and oral phosphorus preparation and sodium bicarbonate were initiated. Acidosis, urinary excretion of Ca, and her bone pain were improved. cCa corrected calcium, P phosphate, Crea creatinine, ALP alkaline phosphatase
To investigate inconsistencies in RTA pathogenesis and the potential of kidney insult involvement, renal biopsy was performed approximately 2 months after the patient’s initial admission to our hospital. Histological analysis of her renal biopsy specimen revealed normal glomerular appearance and minor alterations in the tubulointerstitial area without pathological significance (Figs. 4, 5). There was no deposit, and immune complex nephritis was excluded. Electron microscopy analysis revealed no podocyte foot process effacement with normal glomerular basement membrane and normal endothelial fenestration (Fig. 6). At least, the presence of chronic kidney insults was unlikely; overall mild benign renal sclerosis was suggested. Genetic tests for following genes (SLC4A1, ATP6V1B1, ATP6V0A4, SLC4A4, SLC34A1, CA2, EHHADH, HNF4A, SLC2A2, PHEX, FGF23, DMP1, ENPP1, FAM20C, FGFR1, PTH1R, SLC34A3, SLC9A3R1, CLCN5, OCRL, CYP2R1, HNRNPC, CYP3A4, NF1) were performed and genetic causes of either RTA or hereditary hypophosphatemic rickets were excluded.
Figs. 4–6.
Renal biopsy. The glomeruli were almost normal and no pathological tubulointerstitial abnormalities were observed under light microscopy. No abnormalities in glomerular cells and basement membrane were observed under electron microscope
Discussion
We reported a case of osteomalacia likely induced by atypical RTA with vitamin D deficiency. After treatment with alfacalcidol, oral phosphorus preparation, and sodium bicarbonate, the patient’s bilateral flank pain dramatically improved.
It is important to identify osteomalacia as a cause of bone pain. Fukumoto et al. proposed the diagnostic criteria of osteomalacia [1]. Our patient displayed hypophosphatemia, hypocalcemia, high BAP level, bone pain, low BMD, and multiple areas of uptake confirmed by bone scintigraphy, consistent with the diagnosis of osteomalacia.
RTA is an important causative factor of osteomalacia. Bone alkali salts are consumed for acidosis correction [4, 5]. Osteoclast activation and osteoblast inactivation are confirmed in acidosis [6]. Furthermore, the urinary excretion of Ca and P is increased due to impaired proximal tubular reabsorption, and vitamin D activation is also impaired [7]. These multiple factors impaired mineralization of undifferentiated osteoblasts, resulting in bone fragility and pseudofractures.
This case exhibited impaired renal function with kidney stones. Metabolic acidosis is associated with increased urinary Ca excretion through two mechanisms: release of Ca from bone and changes in Ca transport within the renal tubule [2, 8]. In addition, patients with dRTA present alkaline urine and decreased excretion of citric acid, resulting in urinary stones [9]. Urinary stones and kidney calcification are considered to cause decreased renal function [4]. In this case, renal stones and increased urinary Ca excretion following tubular disorders could have induced renal dysfunction. In addition, her hypercalciuria was worsened when taking alfacalcidol without correction of acidosis (X day on admission), suggesting that the alfacalcidol exacerbated the hypercalciuria by which the tubular function was further deteriorated.
In our patient, both the inadequate acidification of urine and the presence of renal stones strongly supported that dRTA contributed at least in part to her metabolic acidosis. In addition, this patient also exhibited dysfunction of the proximal renal tubule causing impaired reabsorption of the amino acids, urate and phosphate, suggesting the presence of pRTA. Juvenile cases with overlapping distal and proximal RTA have been reported, and this case was considered to be similar to such cases [10]. Two-thirds of dRTA patients have been reported to present with features of partial renal Fanconi syndrome. Most of these patients have mutations in genes related to renal tubule function [10].
Our patient also had vitamin D deficiency, which was one of the causes of osteomalacia. Although we could not completely exclude the presence of a nutritional disorder because of her emaciation, we believed that the decreased renal function-associated RTA was involved in vitamin D deficiency [11, 12]. Vitamin D deficiency could also be involved in her overt proteinuria [13].
In summary, we reported a patient that had severe osteomalacia due to multiple risks, such as RTA and vitamin D deficiency, and hypothalamic hypogonadism accelerated lower BMD (Fig. 7). Her symptoms were dramatically improved by treatment with alfacalcidol, oral phosphorus preparation, and sodium bicarbonate. Even though etiology of her RTA is not yet clear, the sequence of the therapeutic course of this patient indicated that careful assessments of tubular function and acid–base balance are essential for the management of osteomalacia in addition to the evaluation of the Ca/P balance and vitamin D status.
Fig. 7.
Correlation chart. Multiple risks such as renal tubular acidosis, vitamin D deficiency, and hypothalamic hypogonadism were involved in osteomalacia
Compliance with ethical standards
Conflict of interest
KK collaborated with the study in the topic without any association with this manuscript. KK received lecture fees from Daiichi-Sankyo Pharma, Tanabe-Mitsubishi Pharma, Boehringer Ingelheim, Eli Lilly, Sanofi, Taisho Pharma. KK is under a consultancy agreement with Boehringer Ingelheim. MY has received lecture fees from Chugai Pharmaceutical. TI received lecture fees from Kyowa Kirin, Chugai Pharmaceutical, Otsuka Pharmaceutical, Daiichi-Sankyo Company, Terumo Corporation, Teijin Pharma, Japan Blood Products Organization, Novartis Pharma, MSD K.K., Mitsubishi-Tanabe Pharma, and Kissei Pharmaceutical. The other authors declare no conflicts of interest associated with this manuscript.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
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Contributor Information
Masakazu Notsu, Email: mnotsu25@med.shimane-u.ac.jp.
Keizo Kanasaki, Email: kkanasak@med.shimane-u.ac.jp.
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