Etah S. Kurland

Effects of Daily Treatment with Parathyroid Hormone on Bone Microarchitecture and Turnover in Patients with Osteoporosis: A Paired Biopsy Study*

We examined paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant, human parathyroid hormone 1–34 [PTH(1–34)]. Two groups of patients were studied. The first group was comprised of 8 men with an average age 49 years. They were treated with PTH for 18 months. The second group was comprised of 8 postmenopausal women with an average age 54 years. They were treated with PTH for 36 months. The women had been and were maintained on hormone replacement therapy for the duration of PTH treatment. Patients were supplemented to obtain an average daily intake of 1500 mg of elemental calcium and 100 IU of vitamin D. The biopsy specimens were subjected to routine histomorphometric analysis and microcomputed tomography (CT). Cancellous bone area was maintained in both groups. Cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the inner aspect of the cortex in both men and women. This was accompanied by a significant decrease in eroded perimeter on this surface in both groups. Micro‐CT confirmed the foregoing changes and, in addition, revealed an increase in connectivity density, a three dimensional (3D) measure of trabecular connectivity in the majority of patients. These findings indicate that daily PTH treatment exerts anabolic action on cortical bone in patients with osteoporosis and also can improve cancellous bone microarchitecture. The results provide a structural basis for the recent demonstration that PTH treatment reduces the incidence of osteoporosis‐related fractures.

OSTEOPOROSIS AND LOW BONE MASS IN PREMENOPAUSAL AND PERIMENOPAUSAL WOMEN

OBJECTIVE To characterize the historical, clinical, and biochemical features of 111 young women (age, <55 years) referred for evaluation of osteoporosis or low bone mass. METHODS Women with a bone mineral density T score < or = -2.0 (N = 111) at one or more anatomic sites (by dual-energy x-ray absorptiometry) were assessed relative to anthropomorphic and biochemical characteristics and risk factors for osteoporosis. RESULTS Of 111 women with low bone mass or osteoporosis, 73 (66%) had identifiable causes of bone loss, of which estrogen deficiency (menopause, premenopausal estrogen deficiency) and conditions associated with estrogen deficiency (anorexia nervosa, cancer chemotherapy) were the most common. Prolonged use of glucocorticoids was the most common secondary cause of osteoporosis. Of 38 women with no identifiable cause of bone loss, 21 were premenopausal (mean age, 38 +/- 10 years [standard deviation]) and 17 were perimenopausal (mean age, 50 +/- 3 years). The mean lumbar spine T score was -2.18 +/- 1.0 in the premenopausal and -2.51 +/- 0.6 in the perimenopausal women. Nontraumatic fractures were reported by 42% of the premenopausal women and 18% of the perimenopausal women. A family history of osteoporosis was reported by 71% of the premenopausal and 47% of the perimenopausal women. CONCLUSION Most young women with osteoporosis or low bone mass had estrogen deficiency or another secondary cause of premature bone loss (or both). A subset of premenopausal and perimenopausal women, however, had no identifiable cause of bone loss. The strong family history of osteoporosis, especially in the premenopausal women, provides further support for current theories of a genetic predisposition to osteoporosis.

Recovery from skeletal fluorosis (an enigmatic, American case).

A 52‐year‐old man presented with severe neck immobility and radiographic osteosclerosis. Elevated fluoride levels in serum, urine, and iliac crest bone revealed skeletal fluorosis. Nearly a decade of detailed follow‐up documented considerable correction of the disorder after removal of the putative source of fluoride (toothpaste).

Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis

SummaryAnimal models suggest a role for osteonectin/SPARC in determination of bone mass. We found haplotypes consisting of three single nucleotide polymorphisms (SNPs) in the 3′ untranslated region (UTR) of the osteonectin gene are associated with bone density in Caucasian men with idiopathic osteoporosis.IntroductionOsteonectin is a matricellular protein regulating matrix assembly, osteoblast differentiation, and survival. Animal studies indicate that osteonectin is essential for normal bone mass. The 3′ UTR is a regulatory region controlling mRNA stability, trafficking, and translation, and we determined whether osteonectin 3′ UTR haplotypes could be associated with bone mass and/or idiopathic osteoporosis.MethodsSingle strand conformation polymorphism and allele-specific PCR analysis were used to assess alleles at osteonectin cDNA bases 1046, 1599, and 1970, using genomic DNA from middle-aged Caucasian men with idiopathic, low turnover osteoporosis (n = 56) and matched controls (n = 59). Bone density was measured by DXA at spine, hip and radius. Allele and haplotype frequencies were analyzed by Chi square analysis and Fisher’s exact test.ResultsFive common osteonectin 3′ UTR haplotypes were identified. The frequency of one haplotype (1046C-1599C-1970T) was higher in controls compared with patients, and this haplotype was also associated with higher bone densities at multiple sites in patients. In contrast, a second haplotype (1046C-1599G-1970T) was associated with lower bone densities in patients at multiple sites.ConclusionsOsteonectin regulates skeletal remodeling and bone mass in animals, and haplotypes in the 3′ UTR of this gene are associated with bone density in Caucasian men with idiopathic osteoporosis.

Male Skeletal Health and Osteoporosis

Osteoporosis has long been considered to be a disease of the aging female skeleton. As awareness of the pervasiveness of this disorder heightens, men are also being shown to be at risk for osteoporosis. The purpose of this article is to review what is known about the factors in the male that lead to acquisition, maintenance and loss of bone, as well as new insights into a group of men whose osteoporosis, although severe, remains to be explained.

IGF-1 and Osteoporosis: Lessons from Mice and Men

The insulin-like growth factors (IGF-1 and -2) are ubiquitous polypeptides that mediate the activity of growth hormone. In many tissues they serve as paracrine or autocrine factors (1). Second only to the liver, the skeleton is an exceptionally rich source of IGF-1 where it is both synthesized and stored. During bone remodeling, both systemic and skeletal IGF-1 play a major role in the recruitment and differentiation of osteoblasts (2, 3). In the course of bone resorption, the initiating bone remodeling event, matrix-bound IGFs are released and become critical coupling agents linking the processes of bone resorption and bone formation (2). Efforts to establish a relationship between synthesis of rapid bone loss or impaired bone formation and changes in the skeletal or circulatory IGF system have led to several hypotheses suggesting that IGF-1 is of pathophysiologic significance (2). Two recent studies, one showing an age-associated decline in skeletal IGF-1, and the other relating serum IGF-1 to bone density, have strengthened the view that the skeletal IGF regulatory system is important in states of impaired bone remodeling (4, 5). Two additional studies have demonstrated a strong relationship between serum IGF-1 and bone mineral density in men with idiopathic osteoporosis (6, 7). Based on these lines of evidence and the concept that bone density at any age is strongly dependent on peak bone mass, our group has considered IGF-1 to be a key factor in the acquisition of peak bone mass. In this paper, data will be presented which suggest that in several inbred strains of mice and in humans, osteoporotic male idiopathic IGF-1 is an important determinant of bone mineral density (BMD).

Recovery From Skeletal Fluorosis

We appreciate Dr Cundy’s comments about our case report that details partial recovery from skeletal fluorosis during nearly a decade of careful monitoring. His patient provides additional, valuable insights concerning such improvement, including potential differences between sexes. In fact, it is worth highlighting below some of the differences between our observations. First, in our report of a severely affected man, we documented a continued increase in BMD of 3.5% and 6.3% at the lumbar spine (LS) and total hip, respectively, during the year after fluoride (F) exposure apparently ended. Thereafter, a rapid decline and then a slow, continuous drop in BMD was observed. Dr Cundy’s patient did not seem to manifest such anabolic activity of F on her skeleton after F exposure ceased. In our patient, we suggested that his further increase in BMD might have resulted from mineralization of the thick osteoid layer that we documented at diagnosis. Dr Cundy’s patient, with a Z-score of +5.8 in the LS spine after 10 yr of sodium fluoride (NaF) treatment, was more mildly affected than our patient, whose Z-score was +14.3 on referral. Perhaps the degree of osteoidosis in his patient was not enough to cause a detectable, transient, anabolic effect after F withdrawal. Alternatively, the continued increase in BMD in our patient may be a sex effect restricted to men. Or, perhaps calcium supplementation had already helped to mineralize nascent osteoid in Dr Cundy’s patient, or protected her by reducing gut absorption of F by ∼40%. After 10 yr of 40 mg NaF daily (18 mg of F), this woman could have manifested symptomatic skeletal fluorosis. It is uncertain whether calcium supplementation is useful for mitigating the consequences of excessive F exposure, and this should be a consideration for future research with important implications worldwide. Second, Dr Cundy’s observation that cessation of estrogen replacement therapy (9 yr after F exposure) can accelerate bone turnover, with a marked decline of LS BMD, highlights our concern about hypercalciuria and recurrent nephrolithiasis. Based on experience with these two patients, withdrawal of such therapy in the setting of recovery from skeletal fluorosis should be monitored especially carefully, including measurements of urine calcium levels and prophylactic hydration for prevention of possible kidney stones.