Effects of Different Regimens of Sodium Fluoride Treatment for Osteoporosis on the Structure, Remodeling and Mineralization of Bone

We compared initial and final bone histomorphometric findings in 66 osteoporotic patients treated with sodium fluoride (NaF) according to three regimens, and in 7 osteoporotic patients who did not receive NaF. Fourteen patients received continuous NaF 75 mg/day (high-dose) with calcium 1500 mg/day for a mean of 41 months. Twenty-six patients received continuous NaF 50 mg/day (low-dose) with calcium 2000 mg/day for a mean of 15 months, either with (10 patients) or without (16 patients) vitamin D. Twenty-six patients received cyclical low-dose NaF, alternating with vitamin D, for a mean of 15 months and a total treatment duration of 28 months, of whom 14 were and 12 were not on NaF at the time of the second biopsy. Disregarding differences between regimens, there were significant increases in total and mineralized bone volume and trabecular thickness and nonsignificant decreases in these measurements in the control group. Fluoride-induced bone formation was exclusively appositional with no evidence for the creation of new trabeculae. The effect of low-dose NaF on bone structure was the same when the same total dose was given continuously or intermittently, and when the patient was or was not taking vitamin D. The increases in total and mineralized bone volume but not trabecular thickness were greater with high-dose than with low-dose NaF. Low-dose NaF caused modest but significant increases in all osteoid indices, and modest but significant declines in adjusted apposition rate and osteoid maturation rate and no change in bone formation rate. With high-dose NaF, the increase in BV/TV was greater but all indices of osteoid accumulation were much higher and all indices of impaired osteoblast function and mineralization were much lower, and 12 of 14 patients had some form of osteomalacia. This occurred also in 3 of 30 patients treated with low-dose NaF who were not taking vitamin D; the mean increase in osteoid thickness was significantly greater in these patients than in 22 low-dose patients who were taking vitamin D. We conclude: (1) The inconsistent effect of NaF in increasing bone strength is partly due to failure to restore connectivity in patients with severe bone loss and partly due to substantial osteoid accumulation. (2) Even low-dose NaF causes impaired osteoblast function, but this is much greater with high-dose prolonged therapy. (3) There is an unexplained discrepancy between the increase in bone formation implied by increases in spinal bone mineral and the lack of increase in bone formation measured histomorphometrically. (4) Defective mineralization is more closely related to the total cumulative dose of NaF than to the duration of treatment, and with low-dose treatment may be preventable by vitamin D. (5) Future clinical trials should be carried out with smaller doses of NaF and before there has been substantial loss of horizontal trabeculae in the spine. Received: 31 March 1997 / Accepted: 6 February 1998     

A patient with symptomatic osteomalacia associated with Fanconi syndrome

We report a patient with renal tubulointerstitial fibrosis and symptomatic osteomalacia associated with Fanconi syndrome. A 55-year-old woman was hospitalized because of an inability to walk. Beginning approximately 2 years previously, she had experienced gradually worsening pain in the hips, shoulders, and trunk, culminating in a bedridden state. Serum urea nitrogen was 38 mg/dl; creatinine, 2.6 mg/dl; uric acid. 3.6 mg/dl; phosphate, 2.3 mg/dl; and alkaline phosphatase, 2111 IU/l. Urinary β2 microglobulin was 72 331 µg/day. Aminoaciduria, renal glucosuria, and proximal renal tubular acidosis with a normal anion gap were also noted. The patient was diagnosed with Fanconi syndrome. Radiography demonstrated typical Looser zones in the proximal portion of the left and especially the right femoral shaft, and at several other sites. A renal biopsy specimen disclosed severe tubulointerstitial fibrosis with little cellular infiltration. Glomeruli were largely intact. A bone biopsy specimen indicated osteomalacia; no tetracycline labeling could be seen along most trabecular bone surfaces, and the ratio of total osteoid volume to bone volume was increased (71.8%). Bicarbonate administration (9 g/day) gradually lessened most symptoms, permitting ambulation. Calcitriol administration decreased excessive intact-parathyroid hormone emerging after 2 months of acidosis correction. Thus, severe acidosis associated with Fanconi syndrome can induce osteomalacia showing serious skeletal complications, but also responsiveness to bicarbonate therapy.     

Simultaneous, Bilateral Pathological Displaced Intracapsular Hip Fractures Occurring Spontaneously Secondary to Osteomalacia of Hypomagnesemic Origin: A Case Report and Review of the Literature

Abstract   Spontaneous fractures involving both of the femoral necks simultaneously are exceedingly rare events. We report a case of an elderly female who presented after breaking both femoral necks following a trivial fall, initially diagnosed as age-related osteoporosis. Both the hips were treated by hemiarthroplasty. The diagnosis was revised to vitamin D-resistant osteomalacia secondary to hypomagnesemia after histopathological confirmation and further investigations. We examine the different etiological factors and mechanisms operating in the causation of this rare injury and explore the possible role of magnesium in the pathogenesis of osteomalacia. Fractures may remain occult until late, leading to increased morbidity and mortality. The value of an early MRI is recapitulated, with emphasis placed on prevention and early fixation.     

Osteomalacia: The Missing Link in the Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws?

Background. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. Methods. This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. Results. In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. Conclusions. Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.     

Nasal hemangiopericytoma causing oncogenic osteomalacia

Oncogenic osteomalacia is a rare cause that makes abnormalities of bone metabolism. Our case arose in a 47-year-old woman presenting a nasal mass associated with osteomalacia. We excised the mass carefully. After surgery, it was diagnosed as hemangiopericytoma and her symptoms related with osteomalacia were relieved and biochemical abnormalities were restored to normal range. We report and review a rare case of nasal hemangiopericytoma that caused osteomalacia.     

Renal phosphate loss in hereditary and acquired disorders of bone mineralization

Three metabolic bone diseases display similar characteristics such as hypophosphatemia due to chronically elevated renal phosphate clearance, inappropriately low 1,25 (OH)₂ vitamin D serum levels, and variable bone disease (rickets and osteomalacia). X-linked dominant hypophosphatemic rickets (XLH), also called vitamin D-resistant rickets and autosomal dominant hypophosphatemic rickets (ADHR) represent two inherited diseases, whereas oncogenic hypophosphatemia (OHO), also known as tumor induced osteomalacia (TIO), is an acquired paraneoplastic syndrome that, in certain aspects, has much in common with XLH and ADHR. Although the primary causes for these disorders are distinct and well established, their similar features suggest a unifying pathophysiological basis.

This review summarizes what is known about the mechanisms that underlie these diseases and includes most up-to-date information about recently introduced factors that might be involved in the regulation of phosphate homeostasis and skeletal mineralization.     

Gross vertebral collapse associated with long-term disodium etidronate treatment for pelvic Paget’s disease

Inhibition of skeletal mineralisation is a well-recognized complication of disodium etidronate therapy that was identified in the earliest studies of its use in osteoporosis and Paget’s disease. The effect is seen at lower doses in Paget’s disease than in osteoporosis. Several cases of spontaneous fractures occurring in unaffected bones of Paget’s patients have been reported. However, we believe the case described here is the most severe example of etidronate-induced osteomalacia published in the literature, featuring widespread vertebral collapse occurring as a consequence of nearly 10 years of uninterrupted etidronate treatment for isolated hemipelvic Paget’s disease. Received: 9 August 1999 Revision requested: 19 October 1999 Revision received: 6 December 1999 Accepted: 8 December 1999     

Mean wall thickness of trabecular bone packets in the human iliac crest: Changes with age

Summary Four groups (A, B, C, D) of 21-day-old rats were weaned onto a low phosphorus rachitogenic diet and maintained for 149 days. Groups A, B and C received 4 IU oral ergocalciferol (vitamin D₂) supplements in arachis oil every second day. Groups B and C received oral diphenylhydantoin (DPH, 6 g/kg diet; up to 500 mg/kg body weight/day) for 116 and 21 days respectively. At the end of the experiment the width of the osteoid seams in the long term DPH group B were similar to those in the rachitic control group D and both were significantly wider than those in groups A and C (P<0.01).The overall mean serum Ca levels of groups B and D were each significantly lower than those of group A (P<0.005). The serum Ca levels of the group C rats before drug administration were not different from those of group A, but were significantly reduced after administration of DPH (P<0.005).The reduced serum calcium levels of the rats in groups B and D support the histological evidence of osteomalacia in these animals. The reduced serum calcium levels, without increased osteoid in the group C rats, after DPH administration indicate a short term effect of the drug. This work supports the theory that chronic DPH treatment can antagonize the antirachitic effect of calciferol and so produce anticonvulsant osteomalacia in humans and animals.     

低剂量阿德福韦酯致Fanconi综合征和低磷骨软化症1例及文献回顾

A young male patient with a clear diagnosis of chronic hepatitis B, had taken long-term adefovir dipivoxil and lamivudine antiviral therapy. Osteomalacia related symptoms, such as bone pain and walking difficulties appeared 10 months ago. Renal damage related symptoms, such as urine volume change and increased urinary foam appeared 7 months ago. The examination showed signs of osteomalacia after admission, such as duck step, osteoarticular tenderness, thoracic and pelvic compression sign positive. Relevant examinations showed that hypophosphatemic osteomalacia related signs, such as hypophosphatemia, normal blood calcium, elevated blood alkaline phosphatase, no significant decline in active vitamin D3 and intact parathyroid hormone (iPTH). In bone mineral density test, bone fracture line could be noted. Bone scan suggested multiple metabolic lesions. At the same time, there were Fanconi syndrome related performances, such as elevated serum creatinine, decreased blood uric acid, urine glucose positive, elevated urinary and uric acid, urinary protein positive with mainly small molecule proteins, increased renal tubular damage indicators, and the clearance test suggested a decrease in renal tubular reabsorption of phosphorus. Kidney stones could be seen in urinary ultrasound. Therefore, combined with the patient’s clinical manifestations, past history and examinations, we definitely considered his diagnosis was adefovir dipivoxil related renal injury. Adefovir has been widely used for the treatment of chronic hepatitis B. Some studies confirmed that the nephrotoxicity of adefovir, including Fanconi syndrome and hypophosphatemic osteomalacia, was dose-dependent. A daily high-dose of 60-120 mg/d adefovir was concluded in the treatment of human immunodeficiency virus (HIV) infection, inducing nearly 1/2 patients of renal injury. A daily moderate-dose of 30 mg/d adefovir was used for patients in chronic hepatitis B, with nearly 1/3 patients of renal injury. Long-term low-dose adefovir (10 mg/d) used for chronic hepatitis B patients was found to be responsible for renal injury, but the incidence was significantly reduced. We studied this patient and related literature to analyze the pathogenesis, clinical characteristics and treatment outcomes in low-dose adefovir-induced Fanconi syndrome and hypophosphatemic osteomalacia.