An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.

https://jmg.bmj.com/content/jmedgenet/16/2/101.full.pdf

Genetic heterogeneity in osteogenesis imperfecta.

Summary
Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

Efficient tissue regeneration is dependent on the coordinated responses of multiple cell types. Here, we describe a new subpopulation of fibro/adipogenic progenitors (FAPs) resident in muscle tissue but arising from a distinct developmental lineage. Transplantation of purified FAPs results in the generation of ectopic white fat when delivered subcutaneously or intramuscularly in a model of fatty infiltration, but not in healthy muscle, suggesting that the environment controls their engraftment. These cells are quiescent in intact muscle but proliferate efficiently in response to damage. FAPs do not generate myofibres, but enhance the rate of differentiation of primary myogenic progenitors in co-cultivation experiments. In summary, FAPs expand upon damage to provide a transient source of pro-differentiation signals for proliferating myogenic progenitors.

/pdf/muscle-injury-activates-resident-fibro-adipogenic-2eju7mjynb.pdf

Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis

Because of its failure to act when given orally and its rapid hydrolysis when given parenterally, pyrophosphate was used therapeutically only in scintigraphy and against dental calculus. This prompted us to search for analogs that showed similar physicochemical activity but resisted enzymatic hydrolysis and, therefore, would not be degraded metabolically. The bisphosphonates fulfilled these conditions. This review will deal with the mechanisms of action of these compounds. In vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art. Various reviews have been published recently on bisphosphonates and may be consulted also for information on other aspects (8 ‐14). Since the literature in this field is plentiful, selective citation was necessary. Priority is given to papers dealing with the mechanisms of action. Since many papers often deal with the same finding, in most cases only the first ones are quoted. Subsequent papers are quoted only if they convey new knowledge.

/pdf/bisphosphonates-mechanisms-of-action-2dti1bc2gx.pdf

Bisphosphonates: mechanisms of action.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

The estimation of two collagens from human dermis by interrupted gel electrophoresis

Osteoporosis of pregnancy.

Diphosphonates and paget's disease of bone

Osteoporosis in pregnancy is a rare clinical problem of unknown cause. If the bone loss results from the pregnancy alone it should improve toward normal after delivery; in contrast, where bone density was low before pregnancy, due to some other secondary cause, significant postpartum improvement might not be expected. Thirteen women (age 23-37 years) with pregnancy-associated osteoporosis presenting with either pain in the back and vertebral collapse (8 subjects) or pain in the hip (5 subjects) had consecutive dual-energy X-ray absorptiometry measurements of bone mineral density (BMD) for up to 8 years after an affected pregnancy. The BMD results were expressed as a Z-score in relation to an age-matched mean. The mean initial (0-6 months postpartum) BMD was low in both groups and at both sites. In the back pain group the mean spine Z-score (Ll-L4) was -3.34 (range -2.25 to -4.66) and mean total hip Z-score was -2.41 (range -1.44 to -3.82). In the hip pain group the mean spine Z-score was -2.00 (range -1.48 to -2.65) and mean hip Z-score was -2.19 (range -1.12 to -3.26). Subsequent mean hip and spine BMD increased significantly toward the lower end of the normal range. We conclude that a reversible part of the bone loss is related to the pregnancy itself. A low BMD before pregnancy cannot be excluded. Knowledge that the bone density increases after an affected pregnancy, combined with the known rarity of recurrent symptoms in subsequent pregnancies, is important in prognosis.

Roger Smith

Papers

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

The estimation of two collagens from human dermis by interrupted gel electrophoresis

Osteoporosis of pregnancy.

Diphosphonates and paget's disease of bone

Pregnancy-associated osteoporosis: does the skeleton recover?